Omega-3 compositions and methods relating thereto

ABSTRACT

The present invention provides for a water-soluble composition comprising at least one source of Omega-3 comprising at least one Omega-3 fatty acid selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA), and micelle-promoting agents comprising one or more of carrier oils, solvents, emulsifiers and antioxidants, in order to promote an increase in biovailability of the Omega-3 Source of at least two times.

PRIORITY APPLICATION

The present application is the U.S. national phase under 35 U.S.C. 371of international patent application number PCT/AU2017/050850 filed onAug. 11, 2017, which designated the U.S., and which draws priority fromAustralian Patent No. 2016903184, the entirety of which is incorporatedherein by reference.

TECHNICAL FIELD

The present invention generally relates to water-dispersiblecompositions of bioactive lipophilic compounds, particularly relating towater dispersible compositions of fatty acids, their esters andtriglycerides, to compounds useful for the preparation of suchcompositions, to methods of preparing such compounds and compositions,and to the use of such compositions as therapeutics, complementarymedicines and cosmetics.

BACKGROUND

The cells of the small intestine are covered with a microscopically finewater film so that the cells can directly absorb substances that aresoluble in this water film. The bio-availability of water solublesubstances, such as sugar, salts, and certain water-soluble vitamins(for instance Vitamin C) is therefore at an optimum. However, fatsoluble substances—such as fatty acids—are unable to penetrate the waterfilm. Indeed, many important bioactive compounds are highly lipophilicand are suited to dissolution in non-polar solvents, while beingsubstantially insoluble or only partially soluble in aqueous solvents.The lack of solubility of a bioactive compound in aqueous media is animportant factor limiting its therapeutic use or use in clinicalapplications, making it difficult to efficiently administer the compoundto a patient. When administered in the form of an oil solution or somekind of water and/or oil suspension or emulsion, lipophilic compoundstypically show a poor bio-availability, meaning a low concentration anda long build-up time of the compound in the systemic circulation.

The physiological process conducted by the body in an attempt to absorbthese lipophilic compounds of value is known as micelle formation.Through interaction with chemicals carried in bile, the lipophilicspecies can be ‘enveloped’ in a micelle. The chemicals act assurfactants and are molecules formed from a long lipophilic tail with ahydrophilic head. A typical micelle in aqueous solution forms anaggregate with the hydrophilic “head” regions in contact withsurrounding solvent, sequestering the hydrophobic single-tail regions inthe micelle centre. The micelle can then be dispersed in the bulksolvent by virtue of the hydrophilic head groups that form the outerlayer of the micelle.

However, the micelle formation in the small intestine occurs at a timedelay, being after the release of bile secretion (bile juice) andenzymes of the pancreas. Yet the rest of the digestive processes(transport, etc.) continue without interruption during the comparativelylengthy micelle formation process in the small intestine. This resultsin a significant proportion of the micelles being expelled as waste bythe body because the micelles are formed too late in the digestionprocess and thus pass beyond the small intestine. The result of this isa very low bio-availability of fat-soluble substances, being typicallyapproximately 15-25 percent of the consumed amount.

In order to ensure that a sufficient amount of the particular lipophilicsubstances are taken up by the body to actually produce a therapeuticbenefit, they are typically required to be taken in amounts greater than1 gram daily. This is partly due to their low aqueous solubility andthus low ability to be taken up by the body during digestion.

There are also certain people who, due to medical reasons, cannot formmicelles, even further lowering their body's absorption of essentiallipophilic species. Further, old age is also known to reduce the abilityof a person's digestive tract to take up a range of important chemicals,including fatty acids or other lipophilic compounds enclosed inmicelles.

Bioactive lipophilic compounds in need of increased solubility to aid inabsorption by the body can belong to various therapeutic categories,such as certain vitamins, antibiotics, free radical scavengers,immunosuppressants and some fatty acids. Various approaches to achievethe solubility and improve the bio-availability of these and otherlipophilic compounds are known in the prior art, including formation ofwater-soluble complexes. One particularly important class of bioactivelipophilic compound is the Omega-3 fatty acid group—particularly theOmega-3 fatty acids derived from fish oils, such as eicosapentaenoicacid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) andalpha-linolenic acid (ALA). EPA, DHA, DPA and ALA are used, inconjunction with dietary changes, to assist in the lowering andcontinued control of triglyceride levels. EPA is also known orconsidered to be an effective treatment for a number of medicalconditions and has been found to reduce the risk of heart attacks andstrokes, slow the build-up of atherosclerotic plaque and reducingangina. However, the typical Western diet does not typically providesufficient levels of Omega-3 fatty acids, necessitating the use ofsupplements to provide the required amounts.

Therefore it would be advantageous to provide optimised compositions ofbioactive lipophilic compounds, particularly relating to compositions ofOmega-3 fatty acids, including EPA, DHA, DPA and ALA, that provide anincreased bioavailability of the Omega-3 fatty acid. This would overcomeat least some of the disadvantages of previously known approaches inthis field, or would provide a useful alternative.

DISCLOSURE OF INVENTION

These and other advantages are met with the present invention, which inone broad form comprises water-dispersible composition comprising atleast one source of Omega-3, and micelle-promoting agents comprising oneor more of carrier oils, solvents, emulsifiers and antioxidants, whereinthe composition promotes at least a twofold increase in bioavailabilityof the Omega-3 source.

In an embodiment of the present invention, the composition promotes atleast a threefold increase in bioavailability of the Omega-3 source. Ina further embodiment of the present invention, the composition promotesat least a fourfold increase in bioavailability of the Omega-3 source.

In an embodiment of the present invention, the percentage composition ofthe Omega-3 source and at least one micelle-promoting agents is suchthat, dispersed in an aqueous environment, the composition forms apopulation of micelles with a mean population diameter of about 1 to 20micrometres. More preferably, the mean population diameter of themicelles is less than about 15 micrometres. In a preferred embodiment,the mean population diameter of the micelles is greater than about 5micrometres. More preferably, the mean population diameter of themicelles is greater than about 10 micrometres. In a most preferredembodiment of the present invention, the mean population diameter of themicelles is between about 12 to 13 micrometres.

In an embodiment of the present invention, the percentage population ofmicrometres with a diameter of less than 10 micrometres is greater than20%. More preferably, the percentage population of micrometres with adiameter of less than 10 micrometres is greater than 30%. In a mostpreferred embodiment of the present invention, the percentage populationof micrometres with a diameter of less than 10 micrometres is greaterthan 40%.

In an embodiment of the present invention, the Omega-3 Source comprisesat least one Omega 3 fatty acid selected from eicosapentaenoic acid(EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) andalpha-linolenic acid (ALA). Preferably, the Omega 3 fatty acid ispresent in one or more forms selected from fatty acids, ethyl esters,triglycerides and phospholipids.

In an embodiment of the present invention, the carrier oil is selectedfrom one or more of medium chain triglycerides, long chaintriglycerides, caprylic and/or capric triglycerides, coconut oil, cornoil, cottonseed oil, olive oil, sesame oil, soybean oil, peanut oil,castor oil and oleic acid.

In an embodiment of the present invention, the solvent is selected fromone or more of citrus oil, ethanol, ethyl oleate, glycerine, glycerylmono-oleate, limonene, polyethylene glycol 300, polyethylene glycol 400,polyethylene glycol 600 and propylene glycol.

In an embodiment of the present invention, the emulsifier is selectedfrom one or more of hydrogenated castor oil, lecithin, macrogolglycerolhydroxystearate, oat oil polar lipids, phosphatidylcholine, poloxamers,polyoxyl 35 castor oil, polyoxyl 40 castor oil, polysorbate 20,polysorbate 60, polysorbate 80 and polyglycerol esters of fatty acids.

In an embodiment of the present invention, the antioxidant is selectedfrom one or more of Lecithin, ascorbyl palmitate, d alpha-tocopherol,dl-alpha-tocopherol, d-alpha-Tocopheryl acetate, dl-alpha-Tocopherylacetate, d-alpha-Tocopheryl acid succinate, dl alpha-Tocopheryl acidsuccinate, Vitamin E and derivatives thereof, Olive polyphenols andAlgal polyphenols.

In an embodiment of the present invention, the composition furthercomprises an excipient. Preferably, the excipient is selected from oneor more of Colloidal silica, Corn starch, Hydroxypropylmethylcellulose(HPMC), Maltodextrin, Magnesium stearate, Magnesium hydroxide,Microcrystalline cellulose, dextrin, sorbitol, mannitol and Trehalose.

In an embodiment of the present invention, the water-dispersiblecomposition comprises at least one Omega-3 source, from 10% to about 90%by weight, and one or more of at least one carrier oil, up to about 70%by weight; at least one solvent, up to about 20% by weight; at least oneemulsifier, up to about 30% by weight; and at least one antioxidant, upto about 0.01% by weight.

In an embodiment of the present invention, the water-dispersiblecomposition comprises at least one Omega-3 source, from 80% to about 87%by weight, and one or more of at least one carrier oil, up to about 11%by weight; at least one solvent, up to about 10% by weight; at least oneemulsifier, up to about 11% by weight; and at least one antioxidant, upto about 0.1% by weight.

In an embodiment of the present invention, the water-dispersiblecomposition comprises at least one Omega-3 source, at about 87% byweight; at least one solvent, at about 9.75% by weight; and at least oneemulsifier, at about 3.25% by weight.

In an embodiment of the present invention, the water-dispersiblecomposition comprises at least one Omega-3 source, at about 85% byweight; at least one carrier oil, at about 2.25% by weight; at least onesolvent, at about 2.25% by weight; at least one emulsifier, at about10.48% by weight; and at least one antioxidant, at about 0.02% byweight.

In an embodiment of the present invention, the water-dispersiblecomposition comprises at least one Omega-3 source, at about 80% byweight; at least one carrier oil, at about 10.5% by weight; at least oneemulsifier, at about 9.4% by weight; and at least one antioxidant, atabout 0.1% by weight.

In an embodiment of the present invention, the water-dispersiblecomposition comprises at least one Omega-3 source, at about 85% byweight; at least one carrier oil, at about 4.8% by weight; at least onesolvent, at about 4.8% by weight; at least one emulsifier, at about 4.9%by weight; and at least one antioxidant, at about 0.5% by weight.

In an embodiment of the present invention, the water-dispersiblecomposition comprises at least one Omega-3 source, from 5% to about 70%by weight, and one or more of at least one carrier oil, up to about 45%by weight; at least one solvent, up to about 10% by weight; at least oneemulsifier, up to about 15% by weight; and at least one antioxidant, upto about 0.01% by weight; wherein the composition further comprises anexcipient from 30% to about 90% by weight.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described with regards to the followingdrawings, which are as follows:

FIG. 1 is a graphical representation of the percentage uptake of anembodiment of the present invention containing EPA compared to a priorart means of delivering the same;

FIG. 2 is a graphical representation of the percentage uptake of anembodiment of the present invention containing DHA compared to a priorart means of delivering the same;

FIG. 3 is a graph of the population and cumulative population ofmicelles formed through the dispersion of an embodiment of the presentinvention to 200 mg/L in an aqueous solvent; and

FIG. 4 is a graphical representation of the percentage uptake of anembodiment of the present invention with a smaller mean micelle diametercompared to an embodiment of the present invention with a larger meanmicelle diameter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

An aspect of the present invention provides for a water-dispersiblecomposition comprising at least one source of Omega-3 and at least onemicelle-promoting agent comprising one or more of a carrier oil, asolvent, an emulsifier and an antioxidant. In an embodiment of thepresent invention, the water-dispersible composition provides anadvantageous delivery of Omega-3 upon ingestion, resulting in greaterbioavailability of the Omega-3 to the body of the consumer. In anembodiment, this may allow for a greater percentage of the consumedOmega-3 to be absorbed by the body, which may allow for less totalOmega-3 to need to be consumed in order to provide a beneficial effect.

In an embodiment of the present invention, the water-dispersiblecomposition promotes at least a twofold increase in bioavailability ofthe Omega-3 source. This may mean that at least twice as much Omega-3will be taken up by the body when delivered through thewater-dispersible composition of an embodiment of the present invention,compared to prior art means of delivering an equal amount of Omega-3.

In a further embodiment, the composition of the present invention maypromote at least a threefold increase in bioavailability of the Omega-3source. In an even further embodiment, the composition of the presentinvention may promote at least a fourfold increase in bioavailability ofthe Omega-3 source, which may mean that at least four times as muchOmega-3 will be taken up by the body when delivered through thewater-dispersible composition of the present embodiment, compared toprior art means of delivering an equal amount of Omega-3.

In at least one embodiment of the present invention, thewater-dispersible composition is adapted to form into micelles when inan aqueous environment. When the composition of the present invention isadded to water—or a solution largely comprising water, such as milk orfruit juice—The Omega-3 fatty acids and the micelle-promoting agents mayinteract to form a population of micelles. These micelles may be stablewith respect to temperature and acid effects in the stomach and reachthe small intestine undamaged, attach themselves to the mucous membranecells located across the inner surface of the small intestine, and maybe absorbed, thereby leading to higher bio-availability than is the casefor a “normal” fat digestion.

Case Study: Effect of Micelles on Bioavailability

Without wishing to limit the scope of the invention, it is believed thatin order for aqueous-insoluble components (such as Omega-3) to beabsorbed by the body, they need to be enveloped in a micelle that allowsfor the component to be dispersed in an aqueous environment. The micelle“package”, with an outer layer that is adapted to interact with aqueousenvironments, may move through such an environment. In an aqueousenvironment such as that within the stomach and small intestine, themicelle “package” may be able to move to and attach to the mucousmembrane cells located across the inner surface of the small intestine,where they may be easily absorbed by the body. However, the environmentwithin the stomach is not conducive to the creation of micelles, as themicelle-promoting agents are typically present in insufficient amounts.As a result of this, a very large amount of an aqueous-insolublecomponent must typically be consumed in order for a sufficient quantityof it to be absorbed by the body.

The present invention seeks to overcome this by, in at least oneembodiment, providing the necessary agents to promote the formation ofmicelles well before the Omega-3 passes the mucous membrane cells. In atleast one embodiment, the composition of the present invention—upondispersing within an aqueous environment—may arrange into micellescontaining the Omega-3. This may allow for the micelles to be taken upby the body, allowing for the Omega-3 to be absorbed by the body withgreater success. An example clinical trial comparing an embodiment ofthe present invention to a ‘typical’ delivery means of Omega-3 wasconducted. 5 participants (3 males, 2 females) with an average age of 43were included in the trial based on a power calculation to have an 80%chance of detecting a 50% increase in EPA compared to the control.

Inclusion criteria included otherwise healthy men and women between theages of 18-60 years with a BMI lower than 30. Participants were excludedif they had previous history of hematological diseases (e.g., knownsusceptibility to thrombosis), pathological laboratory status (bloodcount, thrombocytes), were on medication for diabetes, heart disease,cholesterol or blood pressure, had known disorders of the of heart,kidney, lung, skin or liver function, diagnosed with cancer, foodallergies or intolerances, or had participated in another study in thelast 6 months.

TABLE 1 Percentage Composition of Micelle-Prepared Capsules Wt. % Commonname/trade name Omega-3 fish oil ethyl ester 87% (72 wt. % EPA, 28 wt. %DHA) Micelle Additive (Composition below) 13% Micelle AdditiveComposition Polysorbate 80 50% Polyoxyl 40 (hyd. castor oil) 25%Polyethylene Glycol 400 12.5%   Citrus oil (>90% d-limonene) 12.5%  

A randomised, cross-over, non-blinded study design was used with a7-week washout period between consumption of each of the treatments.Group A consumed 2 micelle-prepared Omega-3 ethyl ester hard gelatincapsules, with the active ingredients in proportion as per Table 1,above. Each capsule contained 345 mg EPA and 135 mg DHA. A total of 690mg EPA and 270 mg DHA was delivered as a single dose. Group B, thecontrol product, consumed 2 standard Omega-3 ethyl ester hard gelatincapsule. Each capsule containing 345 mg EPA and 135 mg DHA. A total of690 mg EPA and 270 mg DHA was delivered as a single dose. The groupswere reversed after the 7 week wash out period. The treatment dose wasconsumed immediately after taking a fasted blood sample. Blood sampleswere taken at 0, 2, 4, 6, 8 and 24 h for each of the treatment groups.All meals were provided and scheduled and excluded foods with known highOmega-3 content. A list of foods and supplements to be avoided was alsoprovided to all the participants for the evening meal.

EPA and DHA were measured as part of the total fatty acid profile andresults were calculated as change in relative % of EPA & DHA compared tobaseline. Data is presented as means with their standard errors in FIGS.1 and 2—the comparative results for EPA are shown in FIG. 1 and thecomparative results for DHA are shown in FIG. 2. The AUC₀₋₂₄ value (Areaunder the curve from 0 to 24 hours) represents the totalbio-availability of the particular compound over the relevant period oftime and is calculated using the data shown in FIGS. 1 and 2.

As shown in FIG. 1, in both the Micelle and Control groups thepercentage of EPA in the plasma rose steadily from 0 to 8 h with adecrease back to near baseline at 24 hours. C_(max) occurred at 8 hours(Δ 0.406 Micelle-prepared, A 0.124 control). The average percentagechange from baseline EPA concentration was significantly different inthe Micelle group (p=0.0198) with a difference in AUC₀₋₂₄ ofapproximately 4.65 times compared to the control product.

As is shown in FIG. 2, the DHA results had a much higher variation inresults than the EPA with an overall very low uptake in the controlgroup. This may be due to the lower concentration of the initial dose.The average percentage change from baseline DHA concentration wassignificantly different in the Micelle group (p=0.0258) with adifference in AUC₀₋₂₄ of approximately 4.3 times compared to the controlproduct. T_(max) occurred at 4 hours for both groups.

As a result of the above study, it has been shown that at least anembodiment of the present invention may aid in the ability of the bodyto take up Omega-3 fatty acids, with a total bio-availability over a24-hour period that is several times greater than that of an Omega-3supplement absorbed through “normal” digestive processes.

Micelle Diameter

Broadly, the composition of an embodiment of the present invention issuch that, dispersed in an aqueous environment, the majority of micellesso formed will have diameters that are in the low-micrometre range(diameters less than 50 micrometres). In an embodiment of the presentinvention, the percentage composition of the water-dispersiblecomposition is such that, dispersed in an aqueous environment, thecomposition forms a population of micelles with a mean populationdiameter of about 1 to 20 micrometres. In an embodiment, the meanpopulation diameter may be less than about 15 micrometres. In anembodiment, the mean population diameter may be greater than about 5micrometres. In an embodiment, the mean population diameter may begreater than about 10 micrometres. In a further embodiment, the meanpopulation diameter may be between about 12 to 13 micrometres.

In an embodiment of the present invention, the percentage composition ofthe water-dispersible composition is such that, when dispersed in anaqueous environment, at least 50% of the population of micelles may havea diameter less than about 40 micrometres. In an embodiment, at least70% of the population of micelles may have a diameter less than about 40micrometres. In an embodiment, at least 90% of the population ofmicelles may have a diameter less than about 40 micrometres. In anembodiment, at least 95% of the population of micelles may have adiameter less than about 40 micrometres.

In an embodiment of the present invention, the percentage composition ofthe water-dispersible composition is such that, when dispersed in anaqueous environment, at least 20% of the population of micelles may havea diameter less than about 10 micrometres. In an embodiment, at least30% of the population of micelles may have a diameter less than about 10micrometres. In an embodiment, at least 40% of the population ofmicelles may have a diameter less than about 10 micrometres.

In an embodiment of the present invention, the low-micrometre micellesare sufficiently small so as to interact with the mucous membrane cellslining the small intestine.

The micelle population size distribution for an embodiment of thepresent invention dispersed in water to a concentration of 200 mg/L isshown in FIG. 3. In the graph shown therein, the population of micellesthat pass through a particular channel size is shown by the verticallines and is graphed against the left vertical axis, while thecumulative population of micelles that are larger than the channel sizeare graphed by the curved line against the right vertical axis. In theparticular embodiment shown, the population mean micelle diameter isapproximately 12.41 micrometres. In the particular embodiment,approximately 90% of the population of micelles are smaller than 26.67micrometres. In the particular embodiment, approximately 43% of thepopulation of micelles are smaller than 10 micrometres, with 10% of thepopulation of micelles smaller than 1.7 micrometres. The graph of FIG.3, which extends out to a channel size of approximately 150 micrometres,represents the distribution of approximately 99.99% of the micellepopulation formed through the embodiment of the present invention.

Although the experimental data of FIG. 3 is obtained at a compositionconcentration of 200 mg/L in water, the concentration of amicelle-forming substance dispersed in water has minimal effect on thesize of micelles formed by said substance. Therefore, the data shown inFIG. 3 is equally applicable to an embodiment of the present inventiondispersed in an aqueous environment at any therapeutic dosage amount.

From FIG. 3, it can be concluded that at least an embodiment of thepresent invention produces a population of micelles with a meanpopulation diameter between 12 and 13 micrometres.

Case Study: Micelle Diameter and Bio-Availability

The percentage composition of micelle-promoting agents is known todetermine the resulting mean diameter and range of the micellepopulation. It has been further determined that the diameter of aparticular micelle unit is likely to have a distinct and significanteffect on the ability of the body to absorb the micelle. Without wishingto limit the scope of the invention, it is theorised that the smaller amicelle is, the more readily it is taken up by the body.

An example clinical trial utilising different compositions of thepresent invention for delivery of Omega-3 was conducted. 5 participants(3 males, 2 females) with an average age of 43 were included in thetrial based on a power calculation to have an 80% chance of detecting a50% increase in EPA compared to the control. Inclusion criteria includedotherwise healthy men and women between the ages of 18-60 years with aBMI lower than 30. Participants were excluded if they had previoushistory of hematological diseases (e.g., known susceptibility tothrombosis), pathological laboratory status (blood count, thrombocytes),were on medication for diabetes, heart disease, cholesterol or bloodpressure, had known disorders of the of heart, kidney, lung, skin orliver function, diagnosed with cancer, food allergies or intolerances,or had participated in another study in the last 6 months. Theconcentration of Omega-3 fatty acids in the blood plasma of each groupwas measured over a period of 24 hours, the results of which aretabulated below and shown graphically in FIG. 4.

TABLE 2 Blood Plasma Concentration over 24 hours Time (hr) 0 1 2 3 4 5 67 8 24 Conc. Study 1 0 0.12 0.23 0.29 0.35 0.36 0.37 0.39 0.41 0.18Conc. Study 2 0 0.04 0.07 0.11 0.21 0.25 0.3 0.34 — 0.15

The mean size of the micelle population in Conc. Study 1 is 17.7micrometres, while the mean size of the micelle population in Conc.Study 2 is 27.4 micrometres.

TABLE 3 Statistical Results of Clinical Concentration Studies Conc.Conc. Study 1 Study 2 Baseline 0.0 0.0 Total Area (AUC₀₋₂₄) 7.035 5.315Total Peak Area 7.035 5.315 Number of Peaks 1.000 1.000 First X 0.0 0.0Last X 24.00 24.00 Peak X 8.000 7.000 Peak Y 0.4100 0.3400 Area 7.0355.315

As Table 3 above shows, and as shown in the graph of FIG. 4, the AUC₀₋₂₄of the first clinical concentration study is 7.035, while the AUC₀₋₂₄for the second clinical concentration study is 5.315. As micelle sizeincreases, this difference becomes even more apparent; for a mean sizeof approximately 50 micrometres, the AUC₀₋₂₄ is approximately 2.0.Therefore, it is apparent that decreasing micelle size promotes anincreased AUC₀₋₂₄, which is equivalent to an increase in biovailabilityof the delivered Omega-3.

The clear advantage of the present invention is therefore not only inthe provision of Omega-3 through micelles, but in the formation ofmicelles of reduced size in order to improve the ability of the micellesto deliver the Omega-3 to the body.

However, whilst the above example suggests that a decreasing meanmicelle diameter can be inversely linked to an increasing uptake ofOmega-3, there is a limit beyond which this uptake may become dangerous.Every substance, including therapeutic and dietary substances, has atoxicity concentration—a concentration in the body beyond which thesubstance is no longer beneficial and now poses danger to the person.Fat soluble substances, such as Omega-3, are ordinarily of no concern;their uptake is so minimal that an ordinary diet is extremely unlikelyto induce Omega-3 toxicity in a person. The human body can utilisenanometre-scale micelles in the capture of these fat-soluble substancesbecause, as has been discussed previously, the time delay involved inthe natural construction of the micelles means that only a very smallpercentage of the consumed substance will be successfully absorbed bythe body. Therefore, an extremely rapid capture and uptake process isbeneficial.

However, embodiments of the present invention may allow for a far largerproportion of the consumed Omega-3 to be captured and taken up by thebody. There is, therefore, the danger that uptake will be too rapid andmay induce toxicity, particularly if the person is consuming multipletypes of dietary supplements or therapeutic agents.

As is shown in FIGS. 1 & 2, the embodiments of the present inventionhave been determined as providing a balance between the uptake andabsorption of Omega-3 by the body and avoidance of toxicity concerns.The shape of both FIGS. 1 & 2 indicates that the uptake of Omega-3 isboth high and more importantly is consistently high and spread out overa 24-hour period. This may be compared to the potential over-deliverythat may occur with sub-micrometre-scale micelle formation; although theAUC₀₋₂₄ of the resulting graph (for the uptake of Omega-3 delivered bysub-micrometre-scale micelles) may be much higher, it is highly likelythat essentially all of the delivery would occur in a very short periodof time, leading to a massive increase in concentration of Omega-3 inthe body which may reach potentially toxic levels.

The embodiments of the present invention, providing for a population ofmicelles substantially in the range of 0.5-50 micrometres in diameterand with a mean diameter of 1-20 micrometres, have been thus identifiedas providing the safest, most consistent means of delivering atherapeutically-effective dosage of Omega-3 to the human body.

Composition of the Invention

In an embodiment of the present invention, the Omega-3 source maycomprise at least one Omega-3 fatty acid selected from one or more ofeicosapentaenoic acid (EPA), docosahexaenoic acid (DHA),docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA). In anembodiment, the Omega-3 source is an Omega-3 fatty acid that is presentin one or more forms selected from fatty acids, ethyl esters of fattyacids, triglycerides of fatty acids and phospholipids of fatty acids.The source of the Omega-3 fatty acids, such as EPA, DHA, DPA and ALA,may be selected from one or more of fish oil ethyl esters, fish oiltriglycerides, natural fish oils, algae oils, krill oils, green-lippedmussel oil, calamari oil/squid oil and other naturally-occurring Omega-3sources. Different Omega-3 fatty acid sources are approved forpharmaceutical and/or supplementary use in different jurisdictions.Therefore, the source may be changed, or may be present in another formor derivative that is not specifically listed above, without departingfrom the object of the invention.

The skilled person may recognise that Omega-3 sources, such as thoseidentified above, may comprise any number of additional compounds. Theskilled person will understand that the Omega-3 source within thecomposition of the present invention may comprise trace impurities,which may be characteristic impurities of the Omega-3 source.

The question of the presence or absence of trace impurities within theOmega-3 source will be understood by the skilled addressee as having noeffect on the scope of the invention as claimed, provided that thewater-dispersible composition created still fulfils the object of theinvention—that being the creation of a composition providing at leasttwofold increase in bioavailability of Omega-3 through the promotion ofmicelle formation. In other words, the inclusion of an impurity withinthe Omega-3 source that does not inhibit the ability of the resultingcomposition to provide at least a twofold increase in bioavailabilitywould be regarded by the skilled person as being within the scope of theobject of the invention.

In an embodiment, the carrier oil may be selected from one or more ofmedium chain triglycerides, long-chain triglycerides, caprylic and/orcapric triglycerides, coconut oil, corn oil, cottonseed oil, olive oil,sesame oil, soybean oil, peanut oil, castor oil, fish oil and oleicacid.

In an embodiment, the solvent may be selected from one or more of citrusoil, ethanol, ethyl oleate, glycerine, glyceryl mono-oleate, limonene,polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol600 and propylene glycol.

In an embodiment, the emulsifier may be selected from one or more ofhydrogenated castor oil, lecithin, macrogolglycerol hydroxystearate, oatoil polar lipids, phosphatidylcholine, poloxamers, polyoxyl 35 castoroil, polyoxyl 40 castor oil, polysorbate 20, polysorbate 60, polysorbate80 and polyglycerol esters of fatty acids.

In an embodiment, the antioxidant may be selected from one or more ofLecithin, ascorbyl palmitate, d-alpha-tocopherol, dl-alpha-tocopherol,d-alpha-Tocopheryl acetate, dl-alpha-Tocopheryl acetate,d-alpha-Tocopheryl acid succinate, dl-alpha-Tocopheryl acid succinate,Vitamin E and derivatives thereof, Olive polyphenols and Algalpolyphenols.

Not all embodiments may comprise a micelle-promoting agent from allcategories. Certain embodiments may comprise, in addition to the Omega-3source and any other supplementary additives, only a carrier oil, only asolvent, only an emulsifier or only an antioxidant. Certain embodimentsmay comprise any two of the micelle-promoting agent categories. Certainembodiments may comprise any three of the micelle-promoting agentcategories. Compositional ranges for the constituents of someembodiments of the present invention are shown in the table below:

TABLE 4 Percentage Composition Range for Liquid Delivery Component %Composition Omega-3 Fatty Acid 10-90 wt. %  Carrier Oil 0-70 wt. %Solvent 0-20 wt. % Emulsifier 0-30 wt. % Antioxidant 0-0.5 wt. % 

Several example compositions are shown in the table below. Each of thesehave been determined to fulfil at least an object of the invention:

TABLE 5 Example Compositions of an embodiment for Liquid Delivery %Component % Comp. 1 % Comp. 2 % Comp. 3 Comp. 4 Omega-3 Source   87%  85% 80.00%  85.00%  Carrier Oil — 2.26% 10.50%  4.80% Solvent 9.75%2.25% — 4.80% Emulsifier 3.25% 10.47%  9.40% 4.90% Antioxidant — 0.02%0.10% 0.50%

As shown in the table above, not every micelle-promoting agent type isalways needed. In particular, certain forms of micelle-promoting agentof one type may also serve to fulfil the purpose of another type. Forexample, certain carrier oils may also serve as Omega-3 solvents, andvice-versa; likewise, particular solvents may also serve as emulsifiers,and vice-versa; finally, certain carrier oils may also serve asemulsifiers, and vice-versa.

Certain embodiments of the present invention may comprise additionaladditives without departing from the object of the invention, providedthat said object is still met—that being the creation of a compositionproviding at least twofold increase in bioavailability of Omega-3through the promotion of micelle formation.

According to a further embodiment of the invention, a solid compositionmay be produced by allowing the active-ingredient-containing compositionto be adsorbed in or carried on an excipient. Any type of excipientcapable of adsorbing or carrying the liquid composition and acceptablefor oral administration can be used for this purpose. In an embodiment,the excipient may be selected from one or more of colloidal silica, cornstarch, hydroxypropylmethylcellulose (HPMC), maltodextrin, magnesiumstearate, magnesium hydroxide, microcrystalline cellulose, dextrin,sorbitol, mannitol and trehalose.

Different excipients may offer advantages for different uses of thepresent invention. For example, if sorbitol, dextrin and/or mannitol areused as an excipient, the solid composition becomes soluble in water. Iflactose, cornstarch, sorbitol, and/or crystalline cellulose are used,the solid composition acquires plasticity and can be directly compactedinto tablet form. Moreover, chewable tablets, differentially solubletablets, foaming tablets and the like can be prepared accordingly. Inother embodiments of the invention, the composition can be used in thepreparation of liquids, pastes and emulsions. For preparing the solidcomposition, any conventional auxiliaries such as a binder, adisintegrator, a dispersant, an antiseptic and a lubricant may be used.In an embodiment of the present invention, the binder may be one awater-soluble binder such as polyvinylpyrrolidone, hydroxypropylcellulose, polyvinyl alcohol, hydroxypropyl methylcellulose,methylcellulose, Pullulan, syrup, sodium alginate, agar, gelatin,soybean polysaccharide, gum arabic and the like.

The preferable compositional range of the present invention is shown inthe table below for an embodiment of the present invention intended fordelivery in a solid form, such as powders for dissolution or otherpurposes, hard tablets or similar:

TABLE 6 Percentage Composition Range for Solid Delivery Component %Composition Omega-3 Fatty Acid 5-70 wt. % Carrier Oil 0-45 wt. % Solvent0-10 wt. % Emulsifier 0-15 wt. % Antioxidant 0-0.01 wt. %   Excipient30-90 wt. % Method of Production

For the preparation of the composition of this invention, the Omega-3source is combined with one or more of carrier oils, solvents,emulsifiers and antioxidants. The Omega-3 active ingredients derivedfrom the relevant Omega-3 source may be used in either their ‘natural’state as fatty acids, as ethyl esters, as triglycerides or asphospholipids or in the form of one or more other derivatives of Omega-3fatty acids.

The components are combined with the micelle-promoting agents in orderto produce a composition that, when dispersed into an aqueousenvironment, the formation of micelles with a mean diameter of about1-20 micrometres is promoted. An embodiment of the present invention maybe further combined with one or more excipients in order to produce asolid form of the present invention.

An embodiment of the present invention may be directly consumed by aperson or animal as a hard or soft tablet, gel capsule or similar directconsumption means. Alternatively, the embodiment may be combined with anaqueous liquid, such as water, juice or milk, wherein it may bedispersed throughout and then consumed by the person or animal.

While the invention has been described with reference to preferredembodiments above, it will be appreciated by those skilled in the artthat it is not limited to those embodiments, but may be embodied in manyother forms, variations and modifications other than those specificallydescribed. The invention includes all such variation and modifications.The invention also includes all of the steps, features, componentsand/or devices referred to or indicated in the specification,individually or collectively and any and all combinations or any two ormore of the steps or features.

Although the invention has been described with reference to particularchemicals, these identified chemicals should be only regarded asexamples within their particular chemical family as opposed to acomplete and exhaustive list of possible ingredients. The skilled personwill appreciate that unless otherwise specified, the mere substitutionof one particular chemical for another with similar uses, effect,chemical formulae, pharmaceutical capability, biological compatibilityor otherwise similar properties falls within the scope or object of theinvention described herein, and that the scope of the invention includesany and all of these substitute chemicals insofar as the object of theinvention is still fulfilled.

In this specification, unless the context clearly indicates otherwise,the word “comprising” is not intended to have the exclusive meaning ofthe word such as “consisting only of”, but rather has the non-exclusivemeaning, in the sense of “including at least”. The same applies, withcorresponding grammatical changes, to other forms of the word such as“comprise”, etc.

Other definitions for selected terms used herein may be found within thedetailed description of the invention and apply throughout. Unlessotherwise defined, all other scientific and technical terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which the invention belongs.

INDUSTRIAL APPLICABILITY

The present invention may be utilised in relation to compounds andcompositions for use as therapeutics, complementary medicines andcosmetics. In particular, the water-dispersible compounds of the presentinvention, comprising one or more of eicosapentaenoic acid (EPA),docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) andalpha-linolenic acid (ALA) and having high bioavailability, areeffective in clinical, therapeutic, functional food and cosmeticapplication.

The invention claimed is:
 1. A water-dispersible composition comprising:at least one source of Omega-3 fatty acid comprising eicosapentaenoicacid (EPA); and micelle-promoting agents comprising a carrier oil, asolvent, and an emulsifier; wherein the composition comprises up to 70%of the carrier oil by weight and the carrier oil comprises medium chaintriglycerides, wherein the composition comprises up to 20% of thesolvent by weight and the solvent comprises citrus oil, wherein thecomposition comprises up to 30% of the emulsifier by weight and theemulsifier comprises lecithin, and wherein the composition promotes atleast a twofold increase in bioavailability of the Omega-3 fatty acidsource.
 2. The water-dispersible composition of claim 1 wherein thecomposition promotes at least a threefold increase in bioavailability ofthe Omega-3 fatty acid source.
 3. The water-dispersible composition ofclaim 1 wherein the composition promotes at least a fourfold increase inbioavailability of the Omega-3 fatty acid source.
 4. Thewater-dispersible composition of claim 1 wherein the percentagecomposition of the Omega-3 fatty acid source and the at least onemicelle-promoting agent in the water-dispersible composition is suchthat, when dispersed in an aqueous environment, the Omega-3 fatty acidsource and at least one micelle-promoting agent form a population ofmicelles with a mean population diameter of about 1 to 20 micrometers.5. The water-dispersible composition of claim 4 wherein the meanpopulation diameter of the micelles is less than 15 micrometers andgreater than about 5 micrometers when dispersed in an aqueousenvironment.
 6. The water-dispersible composition of claim 5, whereinthe mean population diameter of the micelles is between about 12 to 13micrometers when dispersed in an aqueous environment.
 7. Thewater-dispersible composition of claim 4 wherein the percentagepopulation of micelles with a diameter of less than 10 micrometers isgreater than 20%.
 8. The water-dispersible composition of claim 4,wherein the percentage population of micelles with a diameter of lessthan 10 micrometers is greater than 40%.
 9. The water-dispersiblecomposition according to claim 1, wherein the Omega-3 fatty acid sourcecomprises at least two Omega-3 fatty acids selected fromeicosapentaenoic acid (EPA), docosahexaenoic acid (DHA),docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA).
 10. Thewater-dispersible composition according to claim 9, wherein the Omega-3fatty acid is present in one or more forms selected from fatty acids,ethyl esters, triglycerides and phospholipids.
 11. The water-dispersiblecomposition according to claim 1, wherein the water-dispersiblecomposition further comprises an antioxidant, wherein the antioxidant isselected from one or more of lecithin, ascorbyl palmitate,d-alpha-tocopherol, dl-alpha-tocopherol, d-alpha-Tocopheryl acetate,dl-alpha-Tocopheryl acetate, d-alpha-Tocopheryl acid succinate,dl-alpha-Tocopheryl acid succinate, Vitamin E and derivatives thereof,Olive polyphenols, Algal polyphenols, and mixtures thereof.
 12. Thewater-dispersible composition according to claim 1, further comprisingan excipient.
 13. The water-dispersible composition of claim 12, whereinthe excipient is selected from one or more of Colloidal silica, Comstarch, Hydroxypropylmethylcellulose (HPMC), Maltodextrin, Magnesiumstearate, Magnesium hydroxide, Microcrystalline cellulose, dextrin,sorbitol, mannitol and Trehalose.
 14. A water-dispersible compositionaccording to claim 1, comprising at least one Omega-3 fatty acid source,from 80% to about 87% by weight, and: at least one carrier oil, up toabout 11% by weight; at least one solvent, up to about 10% by weight; atleast one emulsifier, up to about 11% by weight; and at least oneantioxidant, up to about 0.1% by weight.
 15. The water-dispersiblecomposition of claim 14, comprising: the at least one Omega-3 fatty acidsource, at about 87% by weight; the at least one solvent, at about 9.75%by weight; and the at least one emulsifier, at about 3.25% by weight.16. The water-dispersible composition of claim 14, comprising: the atleast one Omega-3 fatty acid source, at about 85% by weight; the atleast one carrier oil, at about 2.25% by weight; the at least onesolvent, at about 2.25% by weight; the at least one emulsifier, at about10.48% by weight; and the at least one antioxidant, at about 0.02% byweight.
 17. The water-dispersible composition of claim 14, comprising:the at least one Omega-3 fatty acid source, at about 80% by weight; theat least one carrier oil, at about 10.5% by weight; the at least oneemulsifier, at about 9.4% by weight; and the at least one antioxidant,at about 0.1% by weight.
 18. The water-dispersible composition of claim14, comprising: the at least one Omega-3 fatty acid source, at about 85%by weight; the at least one carrier oil, at about 4.8% by weight; the atleast one solvent, at about 4.8% by weight; the at least one emulsifier,at about 4.9% by weight; and the at least one antioxidant, at about 0.5%by weight.
 19. The water-dispersible composition of claim 1, comprisingat least one Omega-3 fatty acid source, from 5% to about 70% by weight,and: at least one carrier oil, up to about 45% by weight; at least onesolvent, up to about 10% by weight; at least one emulsifier, up to about15% by weight; and at least one antioxidant, up to about 0.01% byweight; wherein the composition further comprises an excipient from 30%to about 90% by weight.